Lee Tyrey

Treatment of metastatic trophoblastic disease: Good and poor prognosis

Abstract This study reports results of therapy in 91 patients with metastatic gestational trophoblastic disease treated by physicians of the Southeastern Regional Trophoblastic Disease Center. The 91 patients were grouped into good (79 per cent) or poor (19 per cent) prognostic categories. “Poor prognosis” patients were identified by the presence of an initial pretreatment human chorionic gonadotropin (HCG) titer greater than 100,000 I.U. per 24 hours, duration of disease greater than 4 months, or the documentation of cerebral or hepatic metastases. The patients with “good prognosis” metastatic disease were all treated with systemic single agent chemotherapy with methotrexate or actinomycin D. Seventy of these 71 patients were cured. The poor prognosis patients were treated by two treatment protocols. The earlier group of 7 patients in this category were treated with combination chemotherapy only after resistance to conventional single agent methotrexate and actinomycin D had failed to cure the patient. Only one patient surviced. The later group of 10 patients with “poor prognosis” disease were initially treated with combination chemotherapy and 7 were cured. The roles of hysterectomy with chemotherapy, simultaneous liver and/or hepatic irradiation with chemotherapy, and arterially infused chemotherapy are discussed.

Effect of atrazine on ovarian function in the rat

The effect of the chlorotriazine herbicide, atrazine, on ovarian function was studied in Long-Evans hooded (LE-hooded) and Sprague-Dawley (SD) rats. Atrazine was administered by gavage for 21 d to females displaying regular 4-d estrous cycles. In both strains, 75 mg/kg/d disrupted the 4-d ovarian cycle; however, no distinct alteration (i.e., irregular cycles but not persistent estrus or diestrus) was apparent at this dose. At 150 mg/kg/d, atrazine induced repetitive pseudopregnancies in females of both strains. The highest dose tested (300 mg/kg/d) also induced repetitive pseudopregnancies in the SD females, while the ovaries of the LE-hooded female appeared regressed and the smear cytology was indicative of the anestrous condition. Although a NOAEL was not established, the doses employed in this experiment were in excess of those used in chronic feeding studies in which an early onset of mammary gland tumors was noted. These data demonstrate that atrazine can disrupt ovarian function and bring about major changes in the endocrine profile of the female.

Estrous cycle patterns of Sprague-Dawley rats during acute and chronic atrazine administration

An increased incidence or earlier onset of mammary tumors (MT) has been associated with lifetime feeding of atrazine, an agricultural herbicide, to Sprague-Dawley (SD) female rats. Because MT occur spontaneously in this strain, along with episodes of persistent estrus and acyclic estrogen secretion, it was proposed that atrazine may act to promote this process. SD female rats, 7 to 8 wks old, were administered atrazine while vaginal cytology was monitored. At 200 mg/kg/d by gavage, which clearly exceeded the maximum tolerated dose (MTD), the predominant early response was prolonged vaginal diestrus. Persistent estrous episodes were seen, but less commonly. When atrazine was added to the diet, there was likewise an initial appearance of prolonged diestrus at 400 ppm, but by 13 to 14 wks on test (20 to 21 wks of age), persistent estrus was predominant, rising to >50% of animals by 26 wks on test. Age-matched controls also displayed persistent estrus, but to a lesser degree. At 400 ppm atrazine for 6 mo, animals displayed vaginal estrus for a mean of 62.8% of all days, versus 47.3% in age-matched controls, and 20 to 25% in young animals. The 400 ppm dose also exceeded the MTD. Observed no-effect levels for estrous cycling and body weight change were 50 ppm. Significant effects on estrous cycling occurred only at levels previously associated with enhanced or premature MT formation, and suggest that the tumor response in aging SD female rats can be manipulated by factors controlling the internal estrogen milieu. Because atrazine has no intrinsic estrogenic activity, it is more likely that high-level dosing to a susceptible animal model alters control of ovulation and normal cycling. The requirement of excessive dosing levels, as well as differences in neuroendocrine senescence, makes a risk to human health from this mode of action essentially nonexistent.

Modulation of progestin secretion in ovarian cells by 17β-hydroxy-5α-androstan-3-one (dihydrotestosterone): A direct demonstration in monolayer culture

Abstract These studies with a monolayer system of porcine granulosa cells provide a direct demonstration of the ability of androgen to stimulate progestin secretion by ovarian cells. A preferential action of the more potent androgens, dihydrotestosterone and testosterone, was shown but only dihydrotestosterone demonstrated the capacity to stimulate progestin secretion throughout the culture period. Estradiol 17-β markedly depressed progestin synthesis. The results suggest a modulatory role for androgens in the development of full steroidogenic potential by ovarian granulosa cells during follicular development.

Treatment of nonmetastatic gestational trophoblastic disease: Results of methotrexate alone versus methotrexate-folinic acid

Two treatment regimens for nonmetastatic gestational trophoblastic disease are compared in this retrospective study. The course of 39 patients with nonmetastatic gestational trophoblastic disease treated with methotrexate alone is contrasted to that of 29 patients with nonmetastatic gestational trophoblastic disease who were treated with methotrexate alternated with folinic acid. Of those patients initially treated with methotrexate alone, 7.7% developed methotrexate-resistant disease and required a change in chemotherapy for induction of remission. In contrast, 27.5% of patients initially treated with methotrexate and folinic acid developed methotrexate-resistant disease and required a change in chemotherapy to achieve remission. Ultimately, remission was achieved in all patients. Methotrexate as single-agent chemotherapy was found to be consistently more toxic than methotrexate alternated with folinic acid. It is concluded that methotrexate with folinic acid at the dosage used in this study, while less toxic than methotrexate alone, is less effective than methotrexate alone in the induction of remission of nonmetastatic gestational trophoblastic disease.

Ovulation induction with pulsatile gonadotropin-releasing hormone administration in patients with polycystic ovarian syndrome

Gonadotropin-releasing hormone (0.025 microgram/kg) was administered intravenously in a pulsatile fashion to four subjects with polycystic ovary syndrome for a total of six cycles. Five of the six cycles culminated in ovulation, although in one course the response occurred too early to be attributed to the therapy alone. No pregnancies resulted. All luteal phases were of normal duration, but progesterone production as manifested by serum progesterone determination was deficient in some. If additional investigation confirms these preliminary findings, this form of therapy may offer a safe and economic alternative for anovulatory patients refractory to clomiphene citrate therapy. The response of the four subjects suggests that pulsatile gonadotropin-releasing hormone administration may override hypothalamic-pituitary dysfunction and result in ovulatory menstrual cycles.

Reversal of the Delta-9-Tetrahydrocannabinol Inhibitory Effect on Prolactin Secretion by Rostral Deafferentation of the Medial Basal Hypothalamus

The effect of rostral deafferentation of the medial basal hypothalamus (MBH) on delta-9-tetrahydrocannabinol (THC)-induced changes in serum prolactin (PRL) concentrations was investigated in female rats having retrochiasmatic frontal cuts that transected the rostral hypothalamus. Cuts dorsal to the hypothalamus were produced in the same plane in other animals in order to control for possible effects of the surgical procedure or dorsal brain damage. All animals were ovariectomized 28-35 days after stereotaxic surgery to obviate potential confounding effects of differences in ovarian function between groups. Unlesioned rats were ovariectomized to provide a positive control group for THC inhibitory activity. At least 4 weeks after ovariectomy, animals were treated intravenously with THC (0.5 or 1.0 mg/kg body weight) or vehicle at the midpoint of a 110-min experimental period during which blood samples were obtained at 10-min intervals via indwelling atrial cannulae. Serum PRL concentrations were determined by radioimmunoassay and cut locations were confirmed histologically. When administered to ovariectomized animals without brain lesions, THC suppressed serum PRL concentrations from the average treatment level within 30 min (p less than 0.05), and PRL levels remained suppressed for the remainder of the posttreatment sampling period. Treatment with the vehicle alone was without effect. Animals with retrochiasmatic plane cuts that did not transect the rostral hypothalamus similarly displayed PRL suppression in response to THC administration (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The HCG-β-subunit radioimmunoassay: Potential error in HCG measurement related to choice of labeled antigen

Antiserum generated against the hormone-specific beta-subunit of hCG uas used with different labeled antigens to measure circulating hCG in patients having trophoblastic disease. When 125 I-hCGbeta served as the labeled antigen, a small number of patient sera failed to show parallelism with the second IS-hCG reference and erroneous estimates of hormone concentrations were obtained. Replacement of the 125I-hCGbeta with labeled hCG corrected the nonparallelism exhibited by these samples. Inhibition curves obtained with purified hCG and hCGbeta suggested that both the nonparallelism and its correction with the change in labeled antigen would be consistent with the possibility that this assay aberration may result from the presence of free hCGbeta in these sera.

Human chorionic gonadotropin levels in complete and partial hydatidiform moles and in nonmolar abortuses

The rates of regression of human chorionic gonadotropin (hCG) in patients with complete hydatidiform moles, partial hydatidiform moles, and nonmolar abortions were compared. No difference in rates of regression was found among the three groups, but levels of hCG immediately after uterine evacuation were significantly higher in the group with complete hydatidiform moles. Differences in the time required for hCG levels to become undetectable were attributed to the difference in the degree of initial elevation of hCG.

Utility of assay of alpha subunit of human chorionic gonadotropin in management of gestational trophoblastic malignancies

All patients who were treated with chemotherapy for malignant gestational trophoblastic neoplasms at the Southeastern Regional Trophoblastic Disease Center and who experienced remission during the period January 1, 1978, through December 31, 1979, were studied in an attempt to determine if the application of an assay for the alpha subunit of human chorionic gonadotropin (hCG-alpha) could predict those patients who would have recurrences. For each patient, the first three weekly serum samples with undetectable HCG by the hCG beta-subunit radioimmunoassay as well as the two preceding samples with detectable hCG were assayed in a homologous hCG-alpha assay. Results reaffirm previous data that the latter assay is useful only in patients receiving oral contraceptives for suppression of pituitary gonadotropin secretion. No patient who has remained in remission had a mean level of hCG-alpha in the three hCG-negative samples greater than 1 ng/ml. Of those patients who had recurrences of trophoblastic disease, two of three had hCG-alpha levels greater than 1.5 ng/ml. Although these data are preliminary, they suggest that the routine measurement of hCG-alpha in patients successfully treated for trophoblastic disease may aid in identification of a group of patients who require additional or more intensive follow-up and/or additional chemotherapy to prevent later recurrences.